Bob Kronemyer

Ibrexafungerp provides activity against a variety of multidrug-resistant fungi, including 

, according to a review of the pharmacokinetics and pharmacodynamics of the medicine published in the journal 

Ibrexafungerp is a first-in-class triterpenoid antifungal agent in an oral formulation. “Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-d-glucan synthase, a key component of the fungal cell wall, and has both in vitro and in vivo activity against a variety of clinically relevant fungal species, including the yeast 

,” wrote author Matthew William McCarthy, MD, from the Department of Medicine at Weill Cornell Medicine in New York City.

Because the drug retains in vitro activity against both echinocandin-resistant and triazole-resistant strains of pathogenic fungi, it is well positioned to address the mounting challenge of drug-resistant invasive fungal infections.

A single-center, open-label phase I study of healthy subjects that assessed the drug–drug interaction potential between ibrexafungerp and the immunomodulator tacrolimus found that co-administration of the two medicines had no effect on the maximum blood concentrations of tacrolimus.

The study also concluded there was no change in the maximum concentration of tacrolimus in plasma and a 1.4-fold increase in total area under the curve (AUC). This indicates that a dose adjustment for tacrolimus may not be needed when combined with ibrexafungerp, according to McCarthy.

A multicenter, open-label phase II study randomized patients with invasive candidiasis to one of three stepdown therapies: two dosing regimens of oral ibrexafungerp or standard of care following initial echinocandin therapy.

Satisfactory response rates for the study were 86% in the ibrexafungerp 750-mg arm compared to 71% for either ibrexafungerp 500-mg or standard of care. All treatment regimens were also well tolerated.

A population pharmacokinetic analysis of the study concluded that the ibrexafungerp 750-mg regimen leads to target exposure in roughly 85% of the population.

A follow-up phase II, randomized, double-blind, dose-finding study comparing ibrexafungerp to fuconazole for treating VVC found that 1 month after diagnosis, clinical cure rates were higher for ibrexafungerp than for fuconazole: 70% vs. 50%.

The FDA approved ibrexafungerp after two successful randomized, double-blind, placebo-controlled, phase 3 clinical trials.

In one of the two trials, clinical cure, mycological eradication and clinical improvement at day 25 for ibrexafungerp compared to placebo were 51 vs 29%, 50 vs 19% and 64% vs 37%, respectively.

The primary endpoint of the other trial was clinical cure rate, which was defined as the complete resolution of all signs and symptoms at the test-of-cure visit on day 10. Clinical cure, mycological eradication and clinical improvement for ibrexafungerp compared to placebo were 63% vs. 44%, 59% vs. 30% and 72% vs. 55%, respectively.

Ibrexafungerp is currently being investigated for numerous invasive conditions, including fungemia, as either standalone treatment or in combination with other antimicrobial agents.

McCarthy MW. Pharmacokinetics and pharmacodynamics of ibrexafungerp. 

. 2022. 22:9–13. doi:org/10.1007/s40268-021-00376-x

Wring S, Murphy G, Atiee G,et al. Clinical pharmacokinetics and drug–drug interaction potential for coadministered SCY-078, an oral fungicidal glucan synthase inhibitor, and tacrolimus. 

Spec A, Pullman J, Thompson GR, et al. MSG-10: a phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis. 

Azie N, Angulo D, Dehn B, et al. Oral ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis. 

Jallow S, Govender NP. Ibrexafungerp: a first-in-class oral triterpenoid glucan synthase inhibitor. 

Seiler GT, Ostrosky-Zeichner L. Investigational agents for the treatment of resistant yeasts and molds. 

Articles

In June 2021, ibrexafungerp (Brexafemme; Scynexis) became the first drug approved by the U.S. Food and Drug Administration (FDA) in a novel antifungal class in more than 20 years and is now available to treat vulvovaginal candidiasis (VVC).

Treating Vulvovaginal Candidiasis with Ibrexafungerp

Access to immediate postpartum long-acting reversible contraception can improve outcomes. 

 indicates that policies that increase access to immediate postpartum long-acting reversible contraception (LARC) improve birth outcomes.

“The relationship between postpartum contraception, birth intervals and infant outcomes is often assumed, and underscores a lot of family planning research and policy,” said principal investigator Maria Steenland, SD, a research assistant professor at the Population Studies and Training Center, Brown University, Providence, Rhode Island. “However, very little research has investigated the relationship between postpartum family planning and infant outcomes.”

The study focused on South Carolina’s Medicaid program, which in 2012, began to reimburse hospitals for immediate postpartum LARC and separate from the global maternity payment.

A sample of 186,953 Medicaid-paid births in the state between January 2009 and December 2015 were assessed—81,110 births from 2009 to 2011 (prior to policy change); 105,843 births from 2012 to 2015 (post-policy change); and 46,414 births in exposure hospitals (birth in an implementing-policy hospital between 2012 and 2015).

The policy was linked to an absolute 5.6% increase in the overall probability of receiving an immediate postpartum LARC.

Most pronounced was the effect on non-Hispanic Black women, among whom the increase in immediate postpartum LARC was 3.54 percentage points greater than for non-Hispanic White women (

The policy was also associated with a 0.4% decrease in the probability of subsequent preterm birth and a 0.3% reduction in the likelihood of subsequent low birth weight.

However, there were no significant differences in policy and preterm birth or low birth weight between non-Hispanic Black and non-Hispanic White individuals.

Conversely, the policy was linked to a 0.6% decrease in the probability of short-interval birth and a 27-day increase in days to next birth among non-Hispanic Black individuals.

The policy was also associated with a significant decrease in the probability of a subsequent birth within 4 years. “But confidence in this finding is somewhat attenuated by nonparallel trends for this outcome before the policy change,” Steenland told 

The main results of the study do not surprise Steenland because “there are several ways that immediate postpartum LARC could reduce preterm births and low birth weight, such as fewer births overall, fewer short interval births and fewer unintended births.”

The findings of the study are more relevant to policy than to clinical decision-making, according to Steenland, because outcomes of the study were measured among all people who gave birth in a given time period and may be driven by a decrease in the percentage of people who have another birth.

“Future studies examining the effect of waiting 24 months compared to 12 months on infant health, for example, could inform individual decision-making about birth spacing,” she said.

Steenland would like to see policy efforts that expand access to all methods of contraception, including after childbirth hospitalizations though Medicaid expansion, in remaining non-expansion states; maintain federal funding for family planning through Title X; and remove state-level policies that restrict funding to safety-net family planning providers like Planned Parenthood.

“It is also important that immediate postpartum LARC policy implementation be patient-centered and antiracist, so that contraceptive autonomy is not compromised,” said Steenland, who noted that large racial disparities in infant outcomes continue in South Carolina and nationwide.

This article originally appeared on Contemporary Ob/Gyn.

Steenland MW, Pace LE, Cohen JL. Association of Medicaid reimbursement for immediate postpartum long-acting reversible contraception with infant birth outcomes. 

. Published online January 10, 2022. doi:10.1001/jamapediatrics.2021.5688

Immediate Postpartum LARC Access Improves Birth Outcomes

About 1 in 5 girls with pediatric type 2 diabetes (T2D) also has polycystic ovary syndrome (PCOS), according to a systematic review and meta-analysis in JAMA Network Open.

“T2D in youth is on the rise. It is an aggressive disease with high treatment failure rates,” said senior author M. Constantine Samaan, MD, MSc, an associate professor of pediatrics at McMaster University in Hamilton, Ontario, Canada. “While we know that PCOS occurs in girls with T2D, the scale of this condition is not fully known. Our group focused on understanding the global prevalence of PCOS in girls with T2D.”

For the review, the authors devised a search strategy that examined information across several literature databases.

The analysis comprised 470 girls from 6 studies, and the prevalence of PCOS in girls with T2D was 19.58%.

Because heterogeneity among studies was moderate to high, the authors conducted another analysis in which only the studies that reported the exact diagnostic criteria of PCOS were included. This second analysis showed that the prevalence was 24.04%.

“The biggest surprise was that we discovered that girls with T2D were at least twice as likely to have PCOS than those without diabetes,” Samaan told 

In the literature, up to 1 in 9 girls with T2D are diagnosed with PCOS, “but there is a wide range in those figures,” Samaan said. “Our calculation of nearly one in five may in reality be even higher.”

The link between PCOS and T2D in adults is bidirectional, with insulin resistance playing a pivotal role in the pathogenesis of PCOS. “Studies have shown that girls with PCOS have decreased insulin sensitivity and compensatory hyperinsulinemia, which is associated with T2D risk,” Samaan said.

Another potential mechanism that may lead to both insulin resistance and hyperandrogenism is lipotoxicity.

“One of the important findings of the study was that there were no data to determine the association of obesity and race with PCOS risk, which are important associations of T2D,” said Samaan, a staff physician in pediatric endocrinology at McMaster Children's Hospital in Hamilton. “Obesity is considered the main driver of T2D, but some girls with PCOS are neither overweight nor obese. Also, non-Caucasians have a higher risk for T2D than Caucasians.”

But Samaan said the results of the meta-analysis should be cautiously considered because it included studies of larger numbers of girls that did not report the criteria used to diagnose PCOS, “which is a challenge during adolescence.”

Considering that T2D has other associated morbidities, such as fatty liver disease, sleep apnea, abnormal lipids, and hypertension, “the burden of care on these girls is significant,” he said. “Health care providers must be aware of the scale of PCOS in T2D patients, and ask patients about their periods, but also make patients aware of the risk of PCOS with T2D.”

Samaan also noted that it is critical that active screening for PCOS in girls with T2D be initiated at diabetes diagnosis and follows international evidence-based guidelines for diagnosing PCOS in adolescents, as there are treatments that can be offered to manage PCOS.

“In addition, further studies need to estimate some of the drivers of PCOS in these girls, and more molecular studies are required to determine the exact mechanisms of PCOS in T2D,” he said.

Cioana M, Deng J, Nadarajah A, et al. Prevalence of polycystic ovary syndrome in patients with pediatric type 2 diabetes: a systematic review and meta-analysis. 

. Published online February 15, 2022. doi:10.1001/jamanetworkopen.2021.47454

PCOS prevalence in girls with type 2 diabetes was almost 20%.

PCOS Prevalence in Pediatric Diabetes Examined

Patients with acute vulvovaginal candidiasis (VVC) greatly benefited from oral ibrexafungerp (Brexafemme, Scynexis), according to results of a global phase 3 randomized, double-blind, placebo-controlled superiority study published in the international journal of obstetrics and gynecology, BJOG.

Oral ibrexafungerp, which is a semisynthetic, triterpenoid derivative that blocks the synthesis of the fungal cell wall polymer beta-D-glucan, received approval from the U.S. Food and Drug Administration (FDA) in June 2021 and is available by prescription.

The study was conducted between June 2019 and February 2020 at 37 study sites: 19 in the U.S. and 18 in Bulgaria

The 449 female patients in total were all at least 12 years old with acute VVC and a vulvovaginal signs and symptoms (VSS) score of ≥4 at baseline.

Patients were randomly assigned 2:1 to 2 tablets of ibrexafungerp 150 mg or placebo, 2 times daily for 1 day only.

The primary endpoint was the percentage of patients with a clinical cure (VSS = 0) at the test-of-cure visit at mean day 11, for which ibrexafungerp showed a success rate of 63.3% versus 44.0% for placebo (

Secondary endpoints included percentages of patients with mycological eradication; clinical cure and mycological eradication for overall success; clinical improvement of VSS ≤1 at test-of-cure visit; and complete resolution of symptoms at the follow-up visit at mean day 25.

Mycological eradication with ibrexafungerp was 58.5% compared to 29.8% with placebo (

 < 0.001); overall success was 46.1% vs 28.4% (

 = 0.022); and clinical improvement was 72.3% versus 54.8% (

Symptom resolution was also sustained and further increased with ibrexafungerp than with placebo at follow-up: 73.9% vs. 52.4%, respectively (

The drug was generally well tolerated, with adverse events primarily gastrointestinal that were mild to moderate in severity.

“We were pleased to see that this medication was highly effective in treatment of women with acute [VVC],” said Ryan Sobel, MD, a clinical assistant professor of ob/gyn at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania, who is one of the principal investigators in the U.S.

“Ibrexafungerp is a promising novel, well-tolerated and effective oral 1-day treatment for acute VVC,” said Sobel, noting that the first-in-class medication results in an unstable cell wall and the subsequent death of the yeast.

Still, the results of the study “should not and cannot be compared to prior studies using different medications and protocols,” Sobel told 

Nonetheless, for the first time in nearly 2 decades, there is a new orally available antifungal to treat acute VVC, according to Sobel, an attending physician and co-director of the Jefferson Vulvovaginal Health Center in Philadelphia. “For women who are not able to use fluconazole -- which is the only available oral alternative—due to a variety of reasons, such as side effects, allergy and fungal resistance, ibrexafungerp represents a convenient, safe and effective treatment,” he said.

Currently, however, the drug is contraindicated in pregnancy until further data is available. “Also, being a newly patented medication, it is not yet covered by insurance providers, so the cost can be high and may be use-prohibitive for some patients,” Sobel said.

Disclosure: Sobel is a consultant and is on the advisory board and speakers bureau for Scynexis.

Sobel R, Nyirjesy P, Ghannoum MA, et al. Efficacy and safety of oral ibrexafungerp for the treatment of acute vulvovaginal candidiasis: a global phase 3, randomised, placebo-controlled superiority study (VANISH 306). 

Ibrexafungerp is a promising novel, well-tolerated and effective oral 1-day treatment for acute vulvovaginal candidiasis.

Trial Results Indicate Benefit of Oral Ibrexafungerp for Acute VVC

Two PubMed database searches yielded 18 results for inclusion, consisting of clinical trials, observational studies, patient cases, and meta-analyses.

“Historically, it was thought that females with an autoimmune disorder, such as RA, need to be on contraception due to the teratogenicity potential with disease-modifying therapy but no evidence exists about which type of contraception is the most effective and least interacting,” wrote the authors.

Currently-available evidence also indicates no preference for types of contraception in this population; however, it has been shown that COCs might provide contraceptive benefits and potentially other advantages like prolonging the time to disease progression, thus decreasing the debilitating effect of the disease.

Other combination products, such as the ring, have shown similar efficacy but are not recommended for women with RA because they might be difficult to insert, especially in patients with notably decreased dexterity or joint mobility.

No studies have accessed the patch in this population, according to the authors.

Despite studies indicating that women with a RA diagnosis may go into remission for the time of the pregnancy, patient education about this issue is important. Contraception should be considered and prescribed in combination with a patient’s medications to prevent the possibility of an unplanned pregnancy.

Patients on disease-modifying therapy, especially methotrexate, should be on an effective form of contraception agent to prevent pregnancy. Patients with chronic diseases also need to be on contraception when not planning to become pregnant to avoid the risk of unplanned pregnancies with adverse outcomes.

This population favors the withdrawal method or a barrier method, like a condom, for fear of having disease-modifying effects with hormonal contraception. But contraception decisions should be individualized by gynecologists and rheumatologists in consultation with the patient to determine the best option.

For those with RA, the evidence of benefits of COCs has been inconclusive, according to the authors, with no definitive answer. They noted that the benefits seen in prior studies seemed to be strongest before a patient is diagnosed with RA.

One prospective inception cohort study of females with a diagnosis of RA that was published in 

 in 2002 found that those who took COCs for at least 12 years tended to have less radiological joint damage and disability.

 Contraceptives also tended to provide a protective effect in those with more severe forms of the disease, but the sample size was small and lacked power.

Like the above study, most of the clinical trials included in the review were older than 2014, therefore exposing a gap in literature and underscoring the need for more clinical research to confirm or deny efficacy and other possible benefits of COCs in females of childbearing years with an RA diagnosis.

Lopane CM, Comstock B, Nagel AK, et al. Combined oral contraceptive use in rheumatoid arthritis for the purpose of pregnancy prevention and additional benefits: a narrative review. 

. Published online December 8, 2021. doi:org/10.1111/jog.15097

Drossaers-Bakker KW, Zwinderman AH, van Zeben D, et al.Pregnancy and oral contraceptive use do not significantly influence outcome in long term rheumatoid arthritis. 

. 2002 May;61(5):405-8. doi:10.1136/ard.61.5.405

While the use of combined oral contraceptives in patients with rheumatoid and autoimmune disorders have focused on safety, a recent narrative review highlighted the efficacy and benefits of these contraceptives in women with RA. 

Safety, Efficacy of Combined Oral Contraceptives for RA Reviewed

Combined oral contraceptives were found to be moderately more efficacious than placebo for treating overall premenstrual symptomatologyin women with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD), according to a meta-analysis of 9 randomized clinical trials in the 

American Journal of Obstetrics & Gynecology

However, the review concluded that combined oral contraceptives were not effective for treating premenstrual depressive symptoms specifically.

“Oral contraceptives are often considered a treatment option for women with PMS or PMDD, but evidence remains scarce,” said senior author Anouk de Wit, MD, PhD, a clinical epidemiologist at University Medical Center Groningen in the Netherlands. “Therefore we wanted to summarize the existing evidence so clinicians and patients can make well-informed choices about the therapeutic options.”

The authors searched the Cochrane Central Register of Controlled Trials, PubMed, Web of Science, PsycINFO, EMCare, and Embase databases from inception to June 2021.

The 9 eligible studies comprised a total of 1,205 women with either PMS or PMDD. The mean patient age per study ranged from 24.6 to 36.5 years.

The studies examined 9different interventions—8distinct combined oral contraceptives and 1 placebo.

All studies assessed the effect of the premenstrual intervention,administered in the final week before the onset of menses,after 3 months of treatment.

Overall, 4 of the trials were rated as high risk of bias, while the remaining 5 were rated as moderate risk.

None of the combined oral contraceptives were more effective than each other in reducing premenstrual depressive symptoms and overall premenstrual symptomatology.

“Our results challenge the presumed efficacy of oral contraceptives in treating depressive symptoms, which is one of the core complaints of women with PMDD,” de Wit told 

. “Based on these results, women and clinicians can consider oral contraceptives as a treatment for overall premenstrual symptomatology; however, the depressive symptoms will likely not resolve. Hence, other treatment options for such symptoms should be considered.”

For women with PMDD who mostly report depressive symptoms, other popular treatment options might be a more effective approach, such as selective serotonin reuptake inhibitors or cognitive behavioral therapy. “But the certainty of evidence for any available treatment is very low to moderate at best,” de Wit said.

Also, because there is no evidence for 1oral contraceptive being more efficacious than another, “the choice for a specific oral contraceptive should be based on the preferences of the patient and her doctor,” added de Wit.

Contrary to popular belief, the review found no evidence of difference in efficacy among formulations containing drospirenone and other formulations or a 24-day regimen versus other regimens.

“Nonetheless, because drospirenone is linked to an increased risk of blood clots compared to other hormonal contraceptives,preferentially prescribing a drospirenone-containing contraceptive may not be in the patient’s best interest,” de Witt said.

Additionalrandomized clinical trials with head-to-head comparisons of combined oral contraceptives are required to determine which formulation is most effective for premenstrual complaints among women with PMS or PMDD, de Witt concluded.

de Wit AE, de Vries YA, de Boer MK, et al. Efficacy of combined oral contraceptives for depressive symptoms and overall symptomatology in premenstrual syndrome: pairwise and network meta-analysis of randomized trials. Am J Obstet Gynecol. 2021 Dec;225(6):624-633. doi:

Combined oral contraceptives were found to be moderately more efficacious than placebo for treating overall premenstrual symptomatology in women with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD). 